In the field of medicine, many devices are employed which contact body tissue and fluids. These include for example implanted devices, components of blood dialysis devices and blood storage containers. It is important that the surfaces which contact body tissue have certain properties to make them suitable for their function. One of the most important of these is biocompatibility, and non-toxicity to cells. When the device is intended for contact with blood, it is important that the surface of the device does not induce thrombosis. Other considerations are important, depending on the intended use of the device.
For example, in the case of coronary stents, it is desirable that the surface of the stent does not induce inflammatory response, does not promote thrombosis and is rapidly endothelialised. In earlier practice, bare metal stents made from medical steel or other alloys in various designs were predominantly used in coronary stenting procedures. However, following the arterial vessel damage inevitably associated with the stenting operation, smooth muscle cell proliferation and migration into the lumen occurs. This is called restenosis. In 15-20% of operations using a bare metal stent, restenosis leads to serious loss of lumen volume. This requires further medical intervention, commonly re-stenting of the vessel.
In recent years, coronary stents have been modified with polymer coatings which are loaded with drugs, commonly paclitaxel, rapamycin and closely related drugs. These drugs elute from the polymer and inhibit cell migration and neointimal thickening of the arterial wall. Such devices are known as drug-eluting stents. The use of such stents has led to a dramatic reduction in the occurrence of restenosis.
However, certain concerns about the safety of drug-eluting stents have emerged. Late-onset thrombosis leading to death occurs in some patients between 1 and 4 years after implantation of drug eluting stents. For this reason, the proportion of drug eluting stents used in coronary stenting operations has declined in favour of bare metal stents.
The cause of this late onset thrombosis is likely to be that the polymer coating or the combination of polymer and residual drug induces an inflammatory response, leading to platelet adhesion and activation, which triggers the thrombogenic cascade. Paclitaxel and rapamycin diminish restenosis, but they also inhibit endothelial cell proliferation which is necessary for healing of the damaged artery and is protective against thrombosis.
In the light of these problems, the aim of the present invention is to provide improved biocompatible polymeric coatings on stents and other medical devices which are in contact with body tissue.
It is known that extracts of Allium sativum (garlic) have a platelet inhibiting effect (1). In a double-blind, placebo-controlled study on 60 voluntary subjects with cerebrovascular risk factors and constantly increased platelet aggregation, it was demonstrated that the daily ingestion of 800 mg of powdered garlic (in the form of coated tablets) over four weeks led to a significant inhibition of the pathologically increased ratio of circulating platelet aggregates and of spontaneous platelet aggregation.
Some of the compounds in extracts of garlic with anti-inflammatory and platelet inhibiting effects are ajoene, allicin, alliin and ethiin, shown below
See: Bioactive S-alk(en)yl cysteine sulfoxide metabolites in the genus Allium: the chemistry of potential therapeutic agents.    P. Rose, M. Whiteman, P. K. Moore and Y Z Zhu.Nat. Prod. Rep., 2005, 22, 351-368
WO03/018082 discloses an implantable medical device, such as a stent, comprising a substrate and a biocompatible polymeric coating, wherein the coating contains ajoene and/or allicin or isomers, analogues, homologues or derivatives thereof. The biocompatible coating has a composition which permits the ajoene and/or allicin to be controllably released in a predetermined manner and over a prolonged period of time. Therefore, the medical devices disclosed in this document are in the “drug-eluting” category.
U.S. Pat. No. 4,917,921 discloses antithrombogenic and antibiotic compositions for use as coatings on artificial prostheses and implants which remain in contact with blood or other physiological fluids. The compositions are copolymers of 2-vinyl-4H-1,3-dithiin with a biocompatible monomer. The dithiin is a garlic extract having an allyl functionality. Thermal initiation using free-radical initiators, photochemical initiation using photoinitiators, or chemical initiation using group transfer polymerisation with activated methyl-methacrylate are disclosed as possible routes for generating the copolymer. The allyl group is the polymerising part of the monomer, and is therefore not present in the polymer.
The monomer
has been disclosed, as an intermediate in a synthesis of other derivatised pyrroles (2). It is mentioned that this intermediate, along with a number of others, is electropolymerisable.